Anti-Inflammatory Therapy for Atherosclerotic Disease: A Step Closer?

August 27, 2017

Anti-Inflammatory Therapy for Atherosclerotic Disease: A Step Closer?

  1. Karol E. Watson, MD, PhD, FACC

Canakinumab showed modest benefits, but there were also signals of harm and some unexplained results.

  1. Karol E. Watson, MD, PhD, FACC

Inflammation has long been suspected to play a causal role in the pathogenesis of atherosclerosis, but drug trials targeting inflammation have not shown benefit. In an industry-funded, proof-of-concept study (NCT01327846), investigators examined the effect of canakinumab (Ilaris), which is a fully human monoclonal antibody that inhibits interleukin-1β, a cytokine central to the inflammatory response. It is FDA approved for systemic juvenile idiopathic arthritis and cryopyrin-associated periodic syndromes.

The 10,061 participants (mean age, 61) had previous myocardial infarction (MI) and high-sensitivity C-reactive protein levels (hs-CRP) ≥2 mg/L and were randomized to one of three doses of canakinumab (50 mg, 150 mg, or 300 mg) or placebo, administered subcutaneously every 3 months. At 4 years, hs-CRP was reduced more from baseline with all canakinumab doses, in a dose-dependent manner. On the primary endpoint (a composite of nonfatal MI, nonfatal stroke, or cardiovascular death), only the 150-mg dose reached statistical significance (hazard ratio, 0.85). The hazard ratio was similar for the 300-mg dose but was not statistically significant owing to correction for testing multiple doses. The modest benefit for the 150-mg dose was fueled by a lower incidence of nonfatal MI. Compared with placebo, canakinumab was associated with a higher incidence of fatal infection, a lower incidence of cancer death, and no significant difference in all-cause mortality.

Comment

This widely anticipated study delivered some modestly positive results (fewer nonfatal MIs), some worrisome results (increased fatal infections), and some unexpected results (fewer cancer deaths). As a proof-of-concept study for the inflammatory hypothesis of atherothrombosis, it was a success. As a test of the drug canakinumab for treating the disorder, however, the study leaves more questions than answers.

The current cost of canakinumab in the U.S. may be prohibitive of this treatment (≈$65,000 annually at the dosing schedule tested in the trial). The signal for fatal infection requires additional investigation, as does the decrease in cancer deaths. But there now appears to be a new target for antiatherosclerotic therapies. Further research may identify agents with superior antiatherosclerotic benefits, fewer adverse effects, and perhaps additional ancillary positive features.

Editor Disclosures at Time of Publication

  • Disclosures for Karol E. Watson, MD, PhD, FACC at time of publication Consultant / Advisory board: Amarin; Amgen; Boehringer Ingelheim Speaker’s bureau: Boehringer Ingelheim Editorial boards: Reviews in Cardiovascular Medicine; Circulation Quality Outcomes; Circulation

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